It is clear that genes play a significant role in the development of T1D. Progress has been made but several hurdles have impeded progress in defining the functional consequences of the genes associated with T1D risk. These include the modest risk associated with individual genomic regions and uncertainty as to which of the SNPs in these regions are causative limiting mechanistic studies relating genotype to phenotype. The multiplicity of genes and the heterogeneity among individuals poses further complexity to the study of the functional consequences of variation in genes in the human subjects, while murine models may not reflect the impact of a gene on the human immune response. To overcome each of these hurdles we propose a novel strategy to define the functional significance of novel genetic variants in T1D by integrating three different approaches: Aim 1: We will utilize a novel genetic approach to identify causative genetic loci in T1D thus identifying variants that can be studied in a targeted manner in mouse and man. Aim 2: We will model causative variants in mice allowing us to study the impact of the genetic variants on immune development, in multiple cell population and in response to in vivo antigen exposure. Aim 3: We will define the functional phenotypes related to these causative genetic variants in humans with and without T1D. The studies will be in part driven by findings in murine models while they will also determine the relevance of findings from these models to human subjects and T1D. Each aim will be directed by an expert in their field, who has a strong track record for successful collaboration in genotype- phenotype studies of T1D. This approach is unique in that although each Aim will be distinct in its approach findings from each Aim of this project will influence the direction and experimental design of the other aims. The initial studies in Aim 2 and 3 will focus on coding variants already identified through the work of genetic studies; PTPN22, SH2B3, TYK2 and IFIH1. Future studies using this integrated strategy will incorporate genetic variants identified b studies performed in Aim 1- defining addition causative genetic variants associated with T1D. The integration of these approaches will overcome hurdles that now limit progress in T1D genetics, will enhance our understanding of several T1D associated genetic variants, and will also develop a platform for studies of additional genes that will promote a better mechanistic understanding of T1D disease pathogenesis. PUBLIC HEALTH RELEVANCE: T1D is a disease leading to a lifelong requirement for treatment with insulin, and the potential for devastating complications later in life. Genes are known to contribute to the risk of disease, how these genes lead to disease requires an understanding of their functional impact. In this grant we propose a novel strategy that will speed our understanding of how genes known to be associated with T1D lead to this disease; such knowledge will assist future research, but also assist in developing diagnostic and therapeutics for individuals at risk of or with T1D.